Chemical process

ABSTRACT

3-Isochromanone is prepared by partially chlorinating o-tolylacetic acid with sulphuryl chloride or chlorine gas in an inert organic solvent in the presence of a free radical initiator. The 2-chloromethylphenylacetic acid first obtained is converted to 3-isochromanone by treatment with a base and separated from unreacted o-tolylacetic acid, which is in the form of a salt, by a phase separation technique. The separated o-tolylacetic acid salt is converted to o-tolylacetic acid by controlled acidification and the o-tolylacetic acid is extracted for re-use. The invention reduces the formation of unwanted, over-chlorinated by-products and leads to a more efficient process.

This invention relates to a chemical process and more particularly to aprocess for preparing 3-isochromanone, which is useful in themanufacture of certain agrochemicals.

3-Isochromanone is a well-known compound having the formula:

Several methods for its preparation are described in the chemicalliterature. One such method, described in WO 97/48692, involves theradical chlorination of o-tolylacetic acid with sulphuryl chloride toform 2-chloromethylphenylacetic acid, which is then ring-closed using abase to form 3-isochromanone. A similar method is described inEP-A-1072580 where chlorine gas is used instead of sulphuryl chloride.

In WO 97/48692 it is stated that any amount of sulphuryl chloride may beused but, for efficiency, it is desirable to use at least one mole ofsulphuryl chloride per mole of o-tolylacetic acid and preferably a molarexcess up to 1.5 moles per mole. In EP-A-1072580 it is stated that theamount of chlorine gas used is preferably from 0.2 to 2 mol, and morepreferably from 0.8 to 1.2 mol, based on one mol of the o-tolylaceticacid. However, in all the examples 19 g of chlorine is used for 30 g ofo-tolylacetic acid, which is about 1.33 moles per mole. No benefit isclaimed or demonstrated for the use of a lower ratio of chlorine.

An issue with these prior art processes from a commercial viewpoint isthat unwanted, over-chlorinated by-products are formed (such as2-dichloromethylphenylacetic acid and2-chloromethyl-α-chlorophenylacetic acid), thereby reducing theefficiency of the conversion of the o-tolylacetic acid starting materialto 3-isochromanone. The present invention provides an improved processwhich alleviates this problem.

Thus according to the present invention there is provided a process forthe preparation of 3-isochromanone which comprises the steps of:

-   -   (a) partially chlorinating o-tolylacetic acid with sulphuryl        chloride or chlorine gas in an inert organic solvent in the        presence of a free radical initiator to form a reaction mixture        containing 2-chloromethylphenylacetic acid and unreacted        o-tolylacetic acid;    -   (b) treating the reaction mixture from step (a) with an aqueous        salt-forming base to convert the 2-chloromethylphenylacetic acid        to 3-isochromanone and to form a salt of the unreacted        o-tolylacetic acid, preferably in the presence of a catalytic        amount of potassium iodide;    -   (c) separating the 3-isochromanone from the salt of        o-tolylacetic acid obtained in step (b) by a phase separation        technique, the 3-isochromanone being dissolved in a        water-immiscible organic solvent and the o-tolylacetic acid salt        being dissolved in an aqueous solution; and    -   (d) converting the separated o-tolylacetic acid salt to        o-tolylacetic acid by controlled acidification of the aqueous        solution separated in step (c), extracting the o-tolylacetic        acid so formed into a solvent suitable for use in step (a) and        recycling the solvent extract in a subsequent operation of step        (a).

The inert organic solvent employed in step (a) and step (d) of theprocess is inert to the reactants and is of a type suitable for use withfree radical chlorination reactions. Depending on how step (b) of theprocess is carried out (as discussed later), it is preferred to use awater-immiscible inert organic solvent. Such solvents include, forexample, aromatic hydrocarbons such as benzene or halogenated orpolyhalogenated aromatic hydrocarbons such as monochlorobenzene,dichlorobenzenes, for example, o-dichlorobenzene, trichlorobenzenes,monofluorobenzene, trifluoromethylbenzene, bistrifluoromethylbenzenesand chlorotrifluoromethylbenzenes.

The partial chlorination reaction is usually carried out at an elevatedtemperature, normally in the range of from 20° C. to 95° C. When thechlorinating agent is sulphuryl chloride the temperature is suitablyfrom 50° C. to 90° C., for example, from 60° C. to 85° C., and typicallyfrom 75° C. to 80° C. When the chlorinating agent is chlorine gas thetemperature is suitably from 40° C. to 85° C., for example, from 60° C.to 85° C., and typically from 75° C. to 80° C.

By partial chlorination is meant the deliberate under-reaction of thechlorinating agent with the o-tolylacetic acid. The object is to ensurethat the major product of the reaction is 2-chloromethylphenylaceticacid with a minimum of over-chlorinated by-products and to recycleunreacted o-tolylacetic acid. This may be achieved by using from 0.2 to1.2 moles of chlorinating agent for each mole of o-tolylacetic acid, forexample, from 0.4 to 1.2 moles per mole, suitably from 0.7 to 1.1 molesper mole, and typically from 0.75 to 0.99 moles per mole ofo-tolylacetic acid.

The free radical initiator maybe a suitable source of heat or light, forexample ultra-violet light, or a chemical compound of a type typicallyused to initiate free radical reactions, such as a peroxide, a peracidor an azo compound. Particularly suitable are 2,2′-azobis(2-methylbutyronitrile) and 2,2′-azobisisobutyronitrile. The quantity ofchemical initiator used is typically from 0.005 to 0.1 moles per mole ofo-tolylacetic acid, for example from 0.01 to 0.05 moles per mole.

The salt-forming base used in step (b) is suitably an alkali or alkalineearth metal hydroxide, phosphate, carbonate, or bicarbonate, forexample, sodium hydroxide, potassium hydroxide, sodium phosphate, sodiumcarbonate, potassium carbonate, sodium bicarbonate or potassiumbicarbonate. The presence of potassium iodide has been found to enhancethe ring closure processes and improve yields.

-   -   Step (b) of the process may be carried out in either of two        ways. Either:    -   (1) the reaction mixture from step (a) is treated with an        aqueous salt-forming base to form directly 3-isochromanone and        an o-tolylacetic acid salt at a controlled pH; or    -   (2) the 2-chloromethylphenylacetic acid and o-tolylacetic acid        are extracted from the reaction mixture from step (a) at high pH        (viz. at a pH above 10, typically above 12) with a strong        aqueous base to give an aqueous solution of an o-tolylacetic        acid salt and a 2-hydroxymethylphenylacetic acid salt, the        aqueous extract suitably acidified to convert the        2-hydroxymethylphenylacetic acid to 3-isochromanone and the        o-tolylacetic acid salt to o-tolylacetic acid, and, in the        presence of an added water-immiscible organic solvent, the pH        adjusted with a salt-forming base to reconvert the o-tolylacetic        acid to an o-tolylacetic acid salt.

In (1), it is important that the inert organic solvent used in step (a)is a water-immiscible immiscible solvent. This is so that the3-isochromanone, which is dissolved in the solvent, may be directlyseparated from the o-tolylacetic acid salt, which is dissolved in theaqueous phase, in step (c) of the process. In this case the pH issuitably adjusted in a range of from 4 to 8, more suitably, in a rangeof from 6 to 8, for example, in a range of from 6 to 7, and typically ina range of from 6.3 to 6.8. At this pH 2-chloromethylphenylacetic acidis converted to 3-isochromanone and a salt of o-tolylacetic acid isformed. The pH adjustment is conveniently carried out using thesalt-forming base, which will normally be an alkali metal or alkalineearth metal base. This may be a strong base, normally a hydroxide, or amild base, such as a bicarbonate, or a combination of the two. Thus, forexample, the pH may be adjusted with an initial charge of sodium or,preferably, potassium hydroxide, followed by a finer adjustment withsodium or, preferably, potassium bicarbonate. Catalytic amounts ofpotassium iodide have been found to enhance the ring closure process.

In (2), a strong aqueous alkali metal or alkaline earth metal base,typically sodium or potassium hydroxide, is used initially to ring closethe 2-chloromethylphenylacetic acid to form 3-isochromanone which, athigh pH, ring opens to form a water soluble 2-hydroxy-methylphenylaceticacid salt, and to extract the 2-hydroxymethylphenylacetic acid and theo-tolylacetic acid salts from the organic reaction mixture obtained instep (a) of the process. The aqueous extract may then be mixed with thesame or a different water-immiscible organic solvent and acidified to apH below 4, suitably to a pH of 1, using, for example, a strong mineralacid such as hydrochloric acid. This converts (ring-closes) the2-hydroxymethylphenylacetic acid to 3-isochromanone and reforms theo-tolylacetic acid from its salt. Controlled basification using asalt-forming base to a pH of from 4 to 8, more suitably, from 6 to 8, asdescribed for (1) above, converts the o-tolylacetic acid to a salt,which dissolves in the aqueous phase, while the 3-isochromanone remainsin solution in the solvent. The organic and aqueous phases may then beseparated in step (c) using conventional liquid phase separationtechniques.

In step (d) of the process, the o-tolylacetic acid salt is convenientlyextracted from the aqueous phase by controlled acidification in thepresence of a water-immiscible solvent suitable for use in step (a) ofthe process. Controlled acidification to a pH of 4 or below, suitably toa pH in the range of from 2 to 4 and especially to a pH in the range offrom 3 to 3.6, converts the o-tolylacetic acid salt to o-tolylaceticacid, which dissolves in the solvent. Unwanted acidic species areretained in the aqueous layer. The solvent, containing dissolvedo-tolylacetic acid, may then be separated from the aqueous phase byconventional liquid phase separation techniques and recycled directly ina subsequent step (a).

Thus, in a typical process, the o-tolylacetic acid is partiallychlorinated with sulphuryl chloride or chlorine gas using the generalprocedures described in WO 97/48692 and EP-A-1072580. When chlorinationhas proceeded as far as desired, for example, when over half of theo-tolylacetic acid has been converted to 2-chloromethylphenylaceticacid, the reaction mixture is held at about 60° C. and water and baseadded to adjust the pH to, for example, 6 to 8, preferably pH 6 to 7.This results in the ring closure of the 2-chloromethylphenylacetic acidto 3-isochromanone and deprotonates the residual o-tolylacetic acid,extracting it into the aqueous layer. Other acid by-products are alsoextracted with it.

The aqueous layer, when acidified in the presence of a substantiallywater-immiscible solvent (e.g. fluorobenzene or chlorobenzene) reformsthe o-tolylacetic acid, which dissolves in the solvent. The solvent maythen be separated from the aqueous layer and directly recycled in thechlorination process. Although a number of complete recycles arepossible, a purge of the recycled stream can be included if impuritiesbuild up. This technique may be used to enhance the yield of3-isochromanone from o-tolylacetic acid by increasing the efficiency ofthe o-tolylacetic acid conversion to 3-isochromanone.

The organic layer containing the 3-isochromanone may be treated in oneof two ways. Either the solvent may be separated from the3-isochromanone, for example by distillation under reduced pressure, andrecovered or recycled. This leaves a melt of 3-isochromanone which canbe purified further, if necessary, by standard techniques, for example,by distillation or by crystallisation (either melt or solventcrystallisation). Or the solvent may be treated with an aqueous base,such as potassium hydroxide, to extract the 3-isochromanone as anaqueous solution of ring opened 3-isochromanone(2-hydroxymethylphenylacetic acid). Separation of the 3-isochromanonefrom the organic layer may be enhanced by multiple extractions or bycounter-current extraction techniques. Acidification of this aqueousextract to pH 1 (giving ring closure to 3-isochromanone) in the presenceof an organic solvent, such as benzene, fluorobenzene, chlorobenzene,xylene, toluene,-methyl-tert-butyl ether, cyclohexanone ordichloromethane, leaves an organic solution of 3-isochromanone which maybe isolated by, for example, solvent evaporation or other conventionaltechniques.

Alternatively, the o-tolylacetic acid, 3-isochromanone and other acidicby-products may be extracted from the reaction mixture obtained in step(a) with, for example, aqueous potassium hydroxide. The aqueous layermay then be mixed with a solvent (e.g. toluene, oxylene, fluorobenzene,etc.) and acidified to pH 1 at, for example, 60° C. to reconvert theaqueous salts to the 3-isochromanone and o-tolylacetic acid. Separationof the o-tolylacetic acid and most other acid species from the3-isochromanone is achieved by adjustment of the solution ofo-tolylacetic acid and 3-isochromanone to a pH of from 4 to 8, forexample from 6 to 8 and preferably from 6 to 7 by the use of asalt-forming base, such as an alkali or alkaline earth metal hydroxide,phosphate, carbonate, or bicarbonate, for example, sodium hydroxide,potassium hydroxide, sodium phosphate, sodium carbonate, potassiumcarbonate, sodium bicarbonate or, typically, potassium bicarbonate. Theresultant aqueous layer may then be recycled and the 3-isochromanone,dissolved in the solvent, may either be used as made or purified bystandard techniques.

The invention is illustrated by the following Examples.

EXAMPLE 1

0-Tolylacetic acid (346.5 g, 2.307 moles) was charged to a glass reactorfitted with stirrer, thermometer condenser and vented to a causticscrubber. Fluorobenzene (476.2 g, 4.96 moles) was added and the contentsheated to 75-80° C. with stirring. To the mixture was added 2,2′-azobis(2-methylbutyronitrile) (8.9 g, 0.046 moles) in fluorobenzene (79.7 g,0.83 moles). Sulphuryl chloride (311.4 g, 2.307 moles) was added over 3hours while maintaining the temperature at 75-80° C. After the additionwas complete, the mixture was held for 1 hour at 75-80° C. Thetemperature was adjusted to 60° C. and 50% potassium hydroxide (180.9 g,1.615 moles) added, followed by potassium iodide (1.53 g, 0.009 moles).The pH was then adjusted to 6.3 using 20% potassium bicarbonate. Aftersettling, the aqueous phase was separated from the organic phase.

The aqueous phase was held for extraction and re-cycle of theo-tolylacetic acid.

The organic phase was distilled to remove the fluorobenzene and leavethe crude 3-isochromanone 286.6 g at 81% strength w/w (equivalent to 232g @100% wt, 1.568 moles) representing a yield of 68% from o-tolylaceticacid.

The aqueous phase (1042 g) was charged to a reaction vessel containingfluorobenzene (524 g, 5.458 moles) and 36% hydrochloric acid (55 g,0.542 moles) was added to reduce the pH to 1.0. The organic and aqueousphases were stirred, allowed to settle and separated. Analysis of theupper fluorobenzene layer (642.2 g) showed it contained 3.1%o-tolylacetic acid (19.9 g, 0.13 moles) equivalent to 6% of the originalcharge. This layer was recycled for use in a subsequent preparation.

EXAMPLE 2

o-Tolylacetic acid (3.96 kg, 26.36 moles) was charged to a 20 litreglass reactor fitted with stirrer, thermometer and condenser and ventedto a caustic scrubber. Chlorobenzene (6 kg, 53.3 moles) was added andthe contents heated to 78-79° C. with stirring. To the mixture was added2,2′-azobis (2-methylbutyronitrile) (0.103 kg, 0.54 moles) inchlorobenzene (0.93 kg, 8.3 moles). Sulphuryl chloride (2.86 kg, 21.34moles) was added over 3 hours while maintaining the temperature at75-80° C. After the addition was complete, the mixture was held for 1hour at 78-80° C. The temperature was adjusted to 60° C. and 50%potassium hydroxide (1.4 kg, 12.5 moles) was added, followed by 30%potassium iodide (0.05 kg, 0.09 moles). The pH was then adjusted to 6.8using 20% potassium bicarbonate (11.2 kg, 22.4 moles). After settling,the aqueous layer was separated from the organic phase. The organicphase was given a further aqueous potassium bicarbonate wash at pH 6.8(4.8 kg containing 0.06 kg, 0.6 moles potassium bicarbonate). The twoaqueous washes were combined for recycling.

The organic phase was distilled to remove some of the chlorobenzene andwater. Methylcyclohexane was added (6 kg, 61.2 moles). The solution of3-isochromanone was cooled to −5° C. and the 3-isochromanone isolated byfiltration followed by washing with methylcyclohexane. The isolated3-isochromanone weighed 1.8 kg (12.2 moles), at 98% strength w/w andcontained less than 1% o-tolylacetic acid. The isolated yield was 45%from the o-tolylacetic acid charged (60% from the o-tolylacetic acidconsumed taking into account the o-tolylacetic acid recovered).

The combined aqueous washes saved for recycling (ca. 15.9 kg) werecharged to a reaction vessel containing chlorobenzene (4 kg, 35.6moles). Hydrochloric acid 32% strength (1.1 kg, 9.6 moles) was added toreduce the pH to 3.5. The phases were then settled and separated.Analysis of the upper chlorobenzene layer showed it containedo-tolylacetic acid (0.96 kg, 6.4 moles) equivalent to 24.2% of theoriginal charge. This layer was re-cycled in a subsequent preparation aspart of the batch charge.

EXAMPLE 3

o-Tolylacetic acid (3.04 kg, 20.3 moles) was charged to a 20 litre glassreactor fitted with stirrer, thermometer and condenser and vented to acaustic scrubber. Chlorobenzene containing re-cycled o-tolylacetic acid(5.23 kg at 18.3% equivalent to 0.96 kg 100%, 6.4 moles) recovered fromExample 2 was added followed by a make up charge of chlorobenzene (1.5kg/13.3 moles) to give a total chlorobenzene charge of 6 kg (53.3moles). The contents were heated to 78-79° C. with stirring. To themixture was added 2,2′-azobis (2-methylbutyronitrile) (0.103 kg, 0.54moles) in chlorobenzene (0.93 kg, 8.3 moles). Sulphuryl chloride (3.28kg, 24.2 moles) was added over 3 hours maintaining the temperature at75-80° C. After the addition was complete, the mixture was held for 1hour at 78-80° C. The temperature was adjusted to 60° C. and 2 kg ofwater were added followed by 50% potassium hydroxide (2 kg, 17.8 moles).Potassium iodide 30% (0.05 kg, 0.09 moles) was added and the pH was thenadjusted to 6.8 using 20% potassium bicarbonate (10.7 kg, 21.5 moles).After settling, the aqueous phase was separated from the organic phasefor extraction and recycling of the o-tolylacetic acid.

The organic phase was distilled to remove some of the chlorobenzene andwater. Methylcyclohexane was added (6 kg, 61.2 moles). The solution of3-isochromanone was cooled to −5° C., the 3-isochromanone isolated byfiltration and washed with methylcyclohexane. The isolated3-isochromanone weighed 1.65 kg (98% strength w/w, 11.15 moles). Theisolated yield was 41% from o-tolylacetic acid charged (58% fromo-tolylacetic acid consumed taking into account the o-tolylacetic acidrecovered).

The aqueous phase saved for recycling (ca. 17.1 kg) was charged to areaction vessel containing chlorobenzene (4 kg, 35.6 moles).Hydrochloric acid 32% strength (1.36 kg, 11.9 moles) was added to reducethe pH to 3.5. The phases were then settled and separated. Analysis ofthe upper chlorobenzene layer showed it to contain o-tolylacetic acid(1.19 kg, 7.9 moles) equivalent to 29.6% of the original charge.

This layer was held for re-cycling in a subsequent preparation as partof the batch charge.

EXAMPLE 4

o-Tolylacetic acid (3.96 kg, 26.4 moles) was charged to a 20 litre glassreactor fitted with stirrer, thermometer, condenser and scrubber.Chlorobenzene (6 kg) was charged to the reaction vessel and the contentsheated to 78-79° C. A solution of 2,2′-azobis (2-methylbutyronitrile)(103 g) in chlorobenzene (930 g) was added to the vessel. This wasfollowed by sulphuryl chloride (2.86 kg, 22.19 moles) added at a steadyrate over 3 hours. After complete addition, the reaction mixture washeld for an hour. Potassium hydroxide (50% w/w solution, 1.4 kg) wasdosed to the reactor to control an exotherm. Potassium iodide (30%aqueous solution, 50 g) was then added. The pH was finally adjusted to6.8 with 20% potassium bicarbonate solution (11.2 kg). The aqueous layerwas separated from the organic layer and recycled. The organic layer waswashed with water (4.5 kg) and the pH adjusted to 6.8 with 20% potassiumbicarbonate solution (0.3 kg). The aqueous layer was separated from theorganic layer and recycled with the first aqueous phase. The organiclayer was distilled to remove water, and some chlorobenzene for recycle.Methylcyclohexane (6 kg) was then added to provide a ratio ofmethylcyclohexane:chlorobenzene of 50:50% w/w. The solution was cooledfrom 65° C. down to −5° C., and purified 3-isochromanone crystallised.The 3-isochromanone formed, 1.79 kg (98% strength w/w, 11.9 mol). Theisolated yield was 1.79 kg at 98% strength w/w, 11.9 mol or 45% oftheory (59% of OTAA consumed taking into account the o-tolylacetic acidrecovered). Both aqueous layers (15.9 kg) were charged to a reactionvessel and chlorobenzene (4 kg) added. The pH was adjusted withconcentrated hydrochloric acid solution (32% w/w, 1.1 kg) to 3.5 and theaqueous layer separated. A sample of the organic layer was sampled andanalysed for o-tolylacetic acid. This indicated that about 0.96 kg ofo-tolylacetic acid was present (24% of the original charge). Alsopresent was about 220 g of 3-isochromanone (5% of the original charge).

EXAMPLE 5

o-Tolylacetic acid (3.96 kg, 26.36 moles) was charged to a 20 litreglass reactor fitted with stirrer, thermometer and condenser and ventedto a caustic scrubber. Chlorobenzene (6 kg, 53.3 moles) was added. Thecontents were heated to 78-79° C. with stirring. To the mixture wasadded 2,2′-azobis (2-methylbutyronitrile) (0.103 kg, 0.54 moles) inchlorobenzene is (0.93 kg, 8.3 moles). Sulphuryl chloride (2.93 kg,21.67 moles) was added over 3 hours maintaining the temperature at75-80° C. After the addition was complete, the mixture was held for 1hour at 78-80° C. The temperature was adjusted to 60° C. and water (0.95kg) was added followed by 50% potassium hydroxide (1.4 kg, 24.96 moles).Potassium iodide 30% (0.05 kg, 0.09 moles) was added and the pH was thenadjusted to 6.8 using 20% potassium bicarbonate (11.21 kg, 22.39 moles).After settling, the aqueous layer was separated from the organic phasefor extraction and recycling of the o-tolylacetic acid.

The organic phase was distilled to remove some of the chlorobenzene andwater. Methylcyclohexane was added (6 kg, 61.2 moles), the chlorobenzeneand methylcyclohexane ratio being 50/50% w/w. The solution was cooled to−5° C., the 3-isochromanone isolated by filtration and washed withmethylcyclohexane. The isolated 3-isochromanone (1.78 kg at 98.1%strength w/w, 11.8 mol) contained less than 0.1% o-tolylacetic acid. Theisolated yield was 44.7% from the o-tolylacetic acid charged, or 58.7%from the o-tolylacetic acid consumed taking into account theo-tolylacetic acid recovered.

The aqueous phase (ca 15.1 kg) was charged to a reaction vesselcontaining chlorobenzene (4 kg, 35.52 moles). Hydrochloric acid 32%strength (1.12 kg, 9.8 moles) was added to adjust the pH to 3.5. Thephases were then settled and separated. The upper chlorobenzene layercontained o-tolylacetic acid (0.94 kg, 6.3 moles, 23.9% of the originalcharge), and 3-isochromanone (0.18 kg, 1.2 moles). This layer was heldfor re-cycling in Example 6 as part of the batch charge.

EXAMPLE 6

o-Tolylacetic acid (3.04 kg, 20.27 moles) was charged to a 20 litreglass reactor fitted with stirrer, thermometer and condenser and ventedto a caustic scrubber. Chlorobenzene containing the re-cycledo-tolylacetic acid from Example 5 (5.23 kg at 17.8% o-tolylacetic acid;0.93 kg at 100%, 6.2 moles) was added followed by a make up charge ofchlorobenzene (2.0 kg, 17.8 moles). The contents were heated to 78-79°C. with stirring. To the mixture was added 2,2′-azobis(2-methylbutyronitrile) (0.103 kg, 0.54 moles) in chlorobenzene (0.93kg, 8.3 moles). Sulphuryl chloride (3.28 kg, 24.3 moles) was added over3.5 hours maintaining the temperature at 75-80° C. After the additionwas complete, the mixture was held for 1 hour at 78-80° C. Thetemperature was adjusted to 60° C. and 2 kg of water was added followedby 50% potassium hydroxide (2 kg, 17.8 moles) Potassium iodide 30% (0.05kg, 0.09 moles) was added and the pH was adjusted to 6.8 using 20%potassium bicarbonate (10.8 kg, 21.6 moles). After settling, the aqueousphase was separated from the organic phase for extraction and re-cyclingof the o-tolylacetic acid.

The organic phase was distilled to remove some of thechlorobenzene/water. Methylcyclohexane was added (6 kg, 61.2 moles), thechlorobenzene/methylcyclohexane ratio being 50/50% w/w. The solution wascooled to −5° C., the 3-isochromanone isolated by filtration and washedwith methylcyclohexane. The isolated 3-isochromanone (1.64 kg at 98.9%strength w/w, 11.0 mol) contained less than 0.1% o-tolylacetic acid. Theisolated yield was 41.4% from the o-tolylacetic acid charged, or 57.7%from the o-tolylacetic acid consumed taking into account theo-tolylacetic acid recovered.

The aqueous phase (ca. 17.1 kg) was charged to a reaction vesselcontaining chlorobenzene (4 kg, 35.6 moles). Hydrochloric acid 32%strength (1.36 kg, 11.9 moles) was added to reduce the pH to 3.5. Thephases were then settled and separated. The organic phase containedo-tolylacetic acid (1.13 kg, 7.5 moles). This layer was held forre-cycling in Example 7 as part of the batch charge.

EXAMPLE 7

o-Tolylacetic acid (2.81 kg, 18.7 moles) was charged to a 20 litre glassreactor fitted with stirrer, thermometer and condenser and vented to acaustic scrubber. Chlorobenzene containing the re-cycled o-tolylaceticacid (5.31 kg at 21.2% o-tolylacetic acid, 1.12 kg, 7.5 moles) was addedfollowed by a make up charge of chlorobenzene (1.89 kg, 16.8 moles) togive a total chlorobenzene charge of 6.1 kg (53.9 moles). The contentswere heated to 78-79° C. with stirring. To the mixture was added2,2′-azobis (2-methylbutyronitrile) (0.103 kg, 0.54 moles) inchlorobenzene (0.93 kg, 8.3 moles). Sulphuryl chloride (3.86 kg, 28.6moles) was added over 4 hours maintaining the temperature at 75-80° C.After the addition was complete, the mixture was held for 1 hour at78-80° C. The temperature was adjusted to 60° C. and 50% potassiumhydroxide added (2 kg, 17.8 moles). Potassium iodide 30% (0.05 kg, 0.09moles) was added and the pH was adjusted to 6.8 using 20% potassiumbicarbonate (10.62 kg, 21.2 moles). After settling, the aqueous phasewas separated from the organic phase for extraction and re-cycling ofthe o-tolylacetic acid.

The organic phase was distilled to remove some of thechlorobenzene/water. Methylcyclohexane was added (5.5 kg, 56 moles), thechlorobenzene/methylcyclohexane ratio being 43/57% w/w. The solution wascooled to −5° C., the 3-isochromanone isolated by filtration and washedwith methylcyclohexane. The isolated 3-isochromanone (2.12 kg at 96.4%strength w/w, 13.8 mol) contained 0.1% o-tolylacetic acid. The isolatedyield was 52.6% from the o-tolylacetic acid charged, or 66.0% from theo-tolylacetic acid consumed taking into account the o-tolylacetic acidrecovered.

The aqueous phase (ca. 16.95 kg) was charged to a reaction vesselcontaining chlorobenzene (4 kg, 35.6 moles). Hydrochloric acid 32%strength (1.07 kg, 9.4 moles) was added to adjust the pH to 3.5. Thephases were then settled and separated. The organic layer containedo-tolylacetic acid (0.79 kg, 5.3 moles). This layer was held forre-cycling in Example 8 as part of the batch charge.

EXAMPLE 8

o-Tolylacetic acid (3.71 kg, 24.7 moles) was charged to a 20 litre glassreactor fitted with stirrer, thermometer and condenser and vented to acaustic scrubber. Chlorobenzene containing the re-cycled o-tolylaceticacid from Example 7 (4.98 kg at 15.9% o-tolylacetic acid, 0.79 kg, 5.3moles) was added followed by a make up charge of chlorobenzene (1.8 kg,16 moles) to give a total chlorobenzene charge of 6.0 kg (53.2 moles).The contents were heated to 78-79° C. with stirring. To the mixture wasadded 2,2′-azobis (2-methylbutyronitrile) (0.103 kg, 0.54 moles) inchlorobenzene (0.93 kg, 8.3 moles). Sulphuryl chloride (4.28 kg, 31.7moles) was added over 4 hours maintaining the temperature at 75-80° C.After the addition was complete, the mixture was held for 1 hour at78-80° C. The temperature was adjusted to 60° C. and 50% potassiumhydroxide added (2 kg, 17.8 moles). Potassium iodide 30% (0.05 kg, 0.09moles) was added and the pH was adjusted to 6.8 using 20% potassiuntbicarbonate (12.52 kg, 25.0 moles). After settling, the aqueous phasewas separated from the organic phase for extraction and re-cycling ofthe o-tolylacetic acid.

The organic phase was distilled to remove some of thechlorobenzene/water. Methylcyclohexane was added (6.0 kg, 61.1 moles),the chlorobenzene/methylcyclohexane ratio being 51/49% w/w. The solutionwas cooled to -−5° C., the 3-isochromanone isolated by filtration andwashed with methylcyclohexane. The isolated 3-isochromanone (2.30 kg at96.7% strength w/w, 15.0) contained 0.1% o-tolylacetic acid. Theisolated yield was 50.0% from the o-tolylacetic acid charged, or 60.1%from the o-tolylacetic acid consumed taking into account theo-tolylacetic acid recovered.

The aqueous phase (ca 17.96 kg) was charged to a reaction vesselcontaining chlorobenzene (5 kg, 44.4 moles). Hydrochloric acid 32%strength (1.11 kg, 9.75 moles) was added to reduce the pH to 3.5. Thephases were settled and separated. The organic layer containedo-tolylacetic acid (0.76 kg, 5.0 moles).

This layer was held for re-cycling in Example 9 as part of the batchcharge.

EXAMPLE 9

o-Tolylacetic acid (4.25 kg, 28.3 moles) was charged to a 20 litre glassreactor fitted with stirrer, thermometer and condenser and vented to acaustic scrubber. Chlorobenzene containing the re-cycled o-tolylaceticacid from Example 8 (5.15 kg at 14.7% o-tolylacetic acid, 0.76 kg, 5.0moles) was added followed by a make up charge of chlorobenzene (1.1 kg,9.8 moles) to give a total charge of chlorobenzene of 5.5 kg (48.8moles). The contents were heated to 78-79° C. with stirring. To themixture was added 2,2′-azobis (2-methylbutyronitrile) (0.103 kg, 0.54moles) in chlorobenzene (0.93 kg, 8.3 moles). Sulphuryl chloride (5.05kg, 37.4 moles) was added over 4 hours maintaining the temperature at75-80° C. After the addition was complete, the mixture was held for 1hour at 78-80° C. The temperature was adjusted to 60° C. and 50%potassium hydroxide added (2.5 kg, 22.3 moles). Potassium iodide 30%(0.05 kg, 0.09 moles) was added and the pH was adjusted to 6.8 using 20%potassium bicarbonate (12.18 kg, 24.3 moles). After settling the aqueousphase was separated from the organic phase for extraction and re-cyclingof the o-tolylacetic acid.

The organic phase was distilled to remove some of thechlorobenzene/water. Methylcyclohexane was added (6.0 kg, 61.1 moles),the chlorobenzene/methylcyclohexane ratio being 56/44% w/w. The solutionwas cooled to −5° C., the 3-isochromanone isolated by filtration andwashed with methylcyclohexane. The isolated 3-isochromanone (3.03 kg at93.2% strength w/w) contained 0.2% o-tolylacetic acid. The isolatedyield was 57.3% from the o-tolylacetic acid charged, or 66.3% from theo-tolylacetic acid consumed taking account of the o-tolylacetic acidrecovered.

The aqueous phase (ca. 16.55 kg) was charged to a reaction vesselcontaining chlorobenzene (5 kg, 44.4 moles). Hydrochloric acid 32%strength (1.01 kg, 8.9 moles) was added to reduce the pH to 3.5. Thephases were then settled and separated. The organic layer containedo-tolylacetic acid (0.67 kg, 4.5 moles).

EXAMPLE 10

o-Tolylacetic acid (199.5 g, 1.33 moles) was charged to a 1 litre glassreactor fitted with stirrer, thermometer and condenser and vented to acaustic scrubber. Chlorobenzene was added (275 g, 2.44 moles). Thecontents were heated to 78-79° C. with stirring. To the mixture wasadded 2,2′-azobis (2-methylbutyronitrile) (5.15 g, 0.027 moles) inchlorobenzene (46.5 g, 0.41 moles). Chlorine (75.5 g, 1.06 moles) wasadded over 3 hours while maintaining the temperature at 75-80° C. Afterthe addition was complete, the mixture was held for 1 hour at 78-80° C.The temperature was adjusted to 60° C. and water (67 g) was addedfollowed by 50% potassium hydroxide (77.2 g, 0.69 moles) Potassiumiodide 30% (2.5 g, 0.0045 moles) was added and the pH was adjusted to6.4 using 20% potassium bicarbonate (448.8 g, 0.897 moles). Aftersettling, the aqueous phase was separated from the organic phase forextraction and re-cycling of the o-tolylacetic acid.

The organic phase was distilled to remove some of thechlorobenzene/water. Methylcyclohexane was added (300 g, 3.06 moles),the chlorobenzene/methylcyclohexane ratio being 50/50% w/w. The solutionwas cooled to −5° C. and the 3-isochromanone isolated by filtrationfollowed by methylcyclohexane washing. The isolated 3-isochromanone (85g at 99.0% strength w/w, 0.57 mol) contained less than 0.1%o-tolylacetic acid. The isolated yield was 42.7% from the o-tolylaceticacid charged, or 58.3% from the o-tolylacetic acid consumed taking intoaccount the o-tolylacetic acid recovered, (63.8% including recovered3-isochromanone).

The aqueous phase (ca. 686 g) was charged to a reaction vesselcontaining chlorobenzene (275 g, 2.44 moles). Hydrochloric acid 32%strength (59.5 g, 0.52 moles) was added to reduce the pH to 3.5. Thephases were then settled and separated. The organic layer containedo-tolylacetic acid (55.3 g, 0.37 moles), and 3-isochromanone (10.8 g,0.07 moles). This layer was held for re-cycling in Example 11 as part ofthe batch charge.

EXAMPLE 11

o-Tolylacetic acid (145.2, 0.967 moles) was charged to a 20 litre glassreactor fitted with stirrer, thermometer and condenser and vented to acaustic scrubber. Chlorobenzene containing the re-cycled o-tolylaceticacid from Example 10 (345 g at 15.8% o-tolylacetic acid; 54.5 g, 0.37moles) was added. The contents were heated to 78-79° C. with stirring.To the mixture was added 2,2′-azobis (2-methylbutyronitrile) (5.15 g,0.027 moles) in chlorobenzene (46.5 g, 0.41 moles). Chlorine (75.5 g,1.063 moles) was added over 3 hours while maintaining the temperature at75-80° C. After the addition was complete, the mixture was held for 1hour at 78-80° C. The temperature was adjusted to 60° C. and water (67g) was added followed by 50% potassium hydroxide (100 g, 0.89 moles).Potassium iodide 30% (2.5 g, 0.0045 moles) was added and the pH wasadjusted to 6.4 using 20% potassium bicarbonate (442 g, 0.88 moles).After settling, the aqueous phase was separated from the organic phasefor extraction and re-cycling of the o-tolylacetic acid.

The organic phase was distilled to remove some of thechlorobenzene/water. Methylcyclohexane was added (250 g, 2.55 moles),the chlorobenzene/methylcyclohexane ratio being 51/49% w/w. The solutionwas cooled to −5° C., the 3-isochromanone isolated by filtration andwashed with methylcyclohexane. The isolated 3-isochromanone (61.0 g at98.3% strength w/w) contained less than 0.1% o-tolylacetic acid. Theisolated yield was 41.8% from the o-tolylacetic acid charged, or 69.9%from the o-tolylacetic acid consumed taking into account theo-tolylacetic acid recovered.

The aqueous phase (ca. 739 g) was charged to a reaction vesselcontaining chlorobenzene (275 g, 2.44 moles). Hydrochloric acid 32%strength (84.2 g, 0.74 moles) was added to reduce the pH to 3.5. Thephases were settled and separated. The organic layer containedo-tolylacetic acid (55.3 g, 0.373 moles) equivalent to 28.1% of theoriginal charge.

EXAMPLE 12

This Example illustrates a distillative work-up of 3-isochromanone

Chlorobenzene (481 g, 4.27 moles) and o-Tolylacetic acid (350 g,2.33moles) were charged to a glass reactor fitted with stirrer,thermometer condenser and vented to a caustic scrubber. Additionalchlorobenzene (102.4 g, 0.91 moles) was added and the contentsazeotropically dried under vacuum at 75-80° C. with stirring (100.4 gremoved). To the mixture was added 2,2′-azobis (2-methylbutyronitrile)(8.95 g, 0.046 moles) in chlorobenzene (80 g, 0.71 moles). Sulphurylchloride (389.2 g, 2.80 moles) was added over 3 hours while maintainingthe temperature at 75-80° C. After the addition was complete, themixture was held for 1 hour at 75-80° C. The temperature was adjusted to60° C. and water (121 g) charged. A 50% potassium hydroxide solution(182 g, 1.625 moles) added, followed by potassium iodide solution (1.5g, 0.009 moles in water (3.5 g)). The pH was adjusted to pH 6.5 using20% potassium bicarbonate (768 g of 20% solution). Additional water (81g) was added and, after settling, the aqueous phase was separated fromthe organic phase.

The chlorobenzene was removed in vacuo and the remaining melt (300 g at81% strength, 72.5% yield) distilled at 145-155° C. and 9 mbar to givethe final product (222 g at 95.5% strength, 1.43 moles, 61.5% yield).

1. A process for the preparation of 3-isochromanone which comprises thesteps of: (a) partially chlorinating o-tolylacetic acid with sulphurylchloride or chlorine gas in an inert organic solvent in the presence ofa free radical initiator to form a reaction mixture containing2-chloromethylphenylacetic acid and unreacted o-tolylacetic acid; (b)treating the reaction mixture from step (a) with an aqueous salt-formingbase to convert the 2-chloromethylphenylacetic acid to 3-isochromanoneand to form a salt of the unreacted o-tolylacetic acid; (c) separatingthe 3-isochromanone from the salt of o-tolylacetic acid obtained in step(b) by a phase separation technique, the 3-isochromanone being dissolvedin a water-immiscible organic solvent and the o-tolylacetic acid saltbeing dissolved in an aqueous solution; and (d) converting the separatedo-tolylacetic acid salt to o-tolylacetic acid by controlledacidification of the aqueous solution separated in step (c), extractingthe o-tolylacetic acid so formed into a solvent suitable for use in step(a) and recycling the solvent extract in a subsequent operation of step(a).
 2. A process according to claim 1 in which the inert organicsolvent is a water-immiscible solvent.
 3. A process according to claim 1in which the partial chlorination reaction is carried out at atemperature in the range of from 20° C. to 95° C.
 4. A process accordingto claim 1 in which the o-tolylacetic acid is partially chlorinated byusing from 0.2 to 1.2 moles of chlorinating agent for each mole ofo-tolylacetic acid.
 5. A process according to claim 1 in which the freeradical initiator is 2,2′-azobis (2-methylbutyronitrile) or2,2′-azobisisobutyronitrile.
 6. A process according to claim 1 in which,in step (b) the reaction mixture from step (a) is treated with anaqueous salt-forming base to form directly 3-isochromanone and ano-tolylacetic acid salt at a controlled pH.
 7. A process according toclaim 6 in which the pH is controlled in the range of from 4 to
 8. 8. Aprocess according to claim 1 in which, in step (b) the2-chloromethylphenylacetic acid and o-tolylacetic acid are extractedfrom the reaction mixture from step (a) at high pH with a strong aqueousbase to give an aqueous solution of an o-tolylacetic acid salt and a2-hydroxymethylphenylacetic acid salt, the aqueous extract acidified toconvert the 2-hydroxymethylphenylacetic acid to 3-isochromanone and theo-tolylacetic acid salt to o-tolylacetic acid, and, in the presence ofan added water-immiscible organic solvent, the pH adjusted with asalt-forming base to reconvert the o-tolylacetic acid to ano-tolylacetic acid salt.
 9. A process according to claim 8 in which thehigh pH is a pH of 12 or more and the o-tolylacetic acid is converted toa salt by adjusting the pH in a range of from 6 to
 8. 10. A processaccording to claim 1 in which step (b) is carried out in the presence ofa catalytic amount of potassium iodide.
 11. A process according to claim1 in which the water immiscible organic solvent containing3-isochromanone obtained from step (c) is separated from the3-isochromanone and recycled in a subsequent operation of the process,leaving a melt of 3-isochromanone which may be further purified.
 12. Aprocess according to claim 1 in which, in step (d), the o-tolylaceticacid salt is extracted from the aqueous phase by acidification in thepresence of a water-immiscible solvent suitable for use in step (a) ofthe process and the solvent, containing dissolved o-tolylacetic acid,separated from the aqueous phase and recycled directly in a subsequentstep (a).